TY - JOUR
T1 - Regulating mitochondrial metabolism by targeting pyruvate dehydrogenase with dichloroacetate, a metabolic messenger
AU - Schoenmann, Nick
AU - Tannenbaum, Nicholas
AU - Hodgeman, Ryan M.
AU - Raju, Raghavan Pillai
N1 - Publisher Copyright:
© 2023 Elsevier B.V.
PY - 2023/10
Y1 - 2023/10
N2 - Dichloroacetate (DCA) is a naturally occurring xenobiotic that has been used as an investigational drug for over 50 years. Originally found to lower blood glucose levels and alter fat metabolism in diabetic rats, this small molecule was found to serve primarily as a pyruvate dehydrogenase kinase inhibitor. Pyruvate dehydrogenase kinase inhibits pyruvate dehydrogenase complex, the catalyst for oxidative decarboxylation of pyruvate to produce acetyl coenzyme A. Several congenital and acquired disease states share a similar pathobiology with respect to glucose homeostasis under distress that leads to a preferential shift from the more efficient oxidative phosphorylation to glycolysis. By reversing this process, DCA can increase available energy and reduce lactic acidosis. The purpose of this review is to examine the literature surrounding this metabolic messenger as it presents exciting opportunities for future investigation and clinical application in therapy including cancer, metabolic disorders, cerebral ischemia, trauma, and sepsis.
AB - Dichloroacetate (DCA) is a naturally occurring xenobiotic that has been used as an investigational drug for over 50 years. Originally found to lower blood glucose levels and alter fat metabolism in diabetic rats, this small molecule was found to serve primarily as a pyruvate dehydrogenase kinase inhibitor. Pyruvate dehydrogenase kinase inhibits pyruvate dehydrogenase complex, the catalyst for oxidative decarboxylation of pyruvate to produce acetyl coenzyme A. Several congenital and acquired disease states share a similar pathobiology with respect to glucose homeostasis under distress that leads to a preferential shift from the more efficient oxidative phosphorylation to glycolysis. By reversing this process, DCA can increase available energy and reduce lactic acidosis. The purpose of this review is to examine the literature surrounding this metabolic messenger as it presents exciting opportunities for future investigation and clinical application in therapy including cancer, metabolic disorders, cerebral ischemia, trauma, and sepsis.
KW - Dichloroacetate
KW - Energetics
KW - Glycolysis
KW - Lactic acidosis
KW - Mitochondria
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U2 - 10.1016/j.bbadis.2023.166769
DO - 10.1016/j.bbadis.2023.166769
M3 - Review article
C2 - 37263447
AN - SCOPUS:85161021687
SN - 0925-4439
VL - 1869
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 7
M1 - 166769
ER -